1. Field of the Invention
This invention relates to the adrenal hormone dehydroepiandrosterone (DHEA, Chemical Abstracts registry number 53-43-0, systematic name 3-beta-hydroxyandrosten-17-one) and to improved compositions and methods for topical administration thereof.
DHEA is the major secretory product of the human adrenal gland and is the most abundant hormone in the body. It is weakly active as a sex hormone but is a precursor within the body for the androgen testosterone in the male and for estrogenic hormones such as estrone and estradiol in the female. Once DHEA is released into the body from the adrenal gland it is converted into the sulfate ester DHEA-S by the liver.
The liver and the kidney are the principal organs involved in clearing steroid hormones from the circulation.
Hepatic metabolism accomplishes two functions for DHEA: a decrease in the biologic activity of the hormone, and an increase in its water solubility, because of conversion to the hydrophilic sulfate form that can be excreted in urine.
Amounts of DHEA in the circulation change with age (Table 1) and it has therefore been postulated that they may be involved in the maturing and aging process in humans.
TABLE 1 ______________________________________ REFERENCE RANGES OF DEHYDROEPIANDROSTERONE SULFATE Age (years) Males, micrograms/ml Females, micrograms/ml ______________________________________ Newborn 1.7-3.6 1.7-3.6 Prepubertal 0.1-0.6 0.1-0.6 Postpubertal-29 1.4-7.9 0.7-4.5 30-39 1.0-7.0 0.5-4.1 40-49 0.9-5.7 0.4-3.5 50-59 0.6-4.1 0.3-2.7 60-69 0.4-3.2 0.2-1.8 70-79 0.3-2.6 0.1-0.9 ______________________________________ Source: Smith Kline Beecham Clinical Laboratories Co.
Blood levels of DHEA-S peak at approximately 20 years of age and then decline past that age in many individuals. Clinical studies have shown a correlation between a decrease in DHEA-S and an increase in age related conditions.
The plasma half-life of free DHEA is under twenty minutes. In its bound form as DHEA-S it dissociates more rapidly from the binding proteins, making them more susceptible to degradation. The episodic secretion of DHEA, combined with this short plasma half-life results in wide fluctuations in plasma free DHEA levels. By contrast, the steroid sulfates (with significantly less biological activity), such as DHEA-S, which bind with high affinity to albumin, are cleared slowly from the circulation and have high stable plasma concentration.
2. Prior Art
El-Rashidy U.S. Pat. No. 4,978,532 discloses a transdermal dosage form for administering dehydroepiandrosterone (DHEA), utilizing a pressure-sensitive medical grade silicone adhesive material which contains DHEA and a permeation enhancer therefor. A "permeation enhancer" is defined as a compound compatible with DHEA that facilitates the uptake of DHEA through the skin and thus enables a therapeutically effective dosage of DHEA to be administered to the patient. The permeation enhancers contemplated are aromatic or aliphatic carbocyclic compounds that have pendant hydroxyl groups, such as butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), a hydroxypropyl-beta-cyclodextrin (HPBCD), and the like, as well as mixtures thereof.
El-Rashidy states that "DHEA in the presently contemplated dosage forms can be administered to lower elevated blood cholesterol levels, for prophylactic or palliative treatment of patients suffering from AIDS, heart disease, obesity, diabetes, and the like afflictions." However, no results of such administration to patients are disclosed.
Loria U.S. Pat. No. 5,206,008 cites such clinical uses of DHEA as topical treatment of patients suffering from psoriasis, gout, and hyperlipemia, and administration to postcoronary patients. Loria further discloses the conversion of DHEA, both in the body and by chemical synthesis, to 5-androstene-3-beta-17-beta-diol and 5-androstene-3-beta-7-beta-17-beta-triol, and teaches the clinical use of these two metabolites in preference to DHEA.
Fawzi et al U.S. Pat. No. 4,783,450 discloses that lecithin enhances the penetration of a drug through the skin as well as a pharmaceutical composition adapted for transdermal administration comprising an active ingredient and an effective amount of lecithin. An active ingredient is defined as "an effective amount of any therapeutically active drug". The "preferred drugs" recited by categories and specific compounds do not include DHEA or any steroid or any kind of hormone.
Hsia et al U.S. Pat. No. 5,231,090 discloses a method of lowering serum cholesterol levels in mammals comprising topically administering a phospholipid containing composition such as lecithin with a pharmaceutically acceptable carrier, which can be "any carrier that does not affect the affinity of the phospholipid for cholesterol". The phospholipid containing composition can be present, for example, in a patch which can be adhered to the skin of the individual such that topical administration is effected. There is no mention of any clinically active material to be used together with lecithin. Hence there is no teaching that a phospholipid is of any benefit in increasing serum levels of any substance.
DuBois U.S. Pat. No. 5,075,113 discloses dietetic, laxative, or cosmetic products which are emulsions of an aqueous phase in an oily phase, in which the aqueous phase contains an extract of hydrodispersible lecithin enriched in phosphatidylcholine, and the oily phase is composed principally of oily paraffin hydrocarbons and a purified lipo-soluble lecithin extract. The products can contain an inert mineral powder such as kaolin, talc or calcium carbonate, and monoglycerides melting above 50.degree. C., as well as a variety of flavors. There is no mention or suggestion of transdermal administration of any therapeutic by using the disclosed composition.
Against this background there remains a need for improved methods and compositions for topically administering DHEA and achieving novel therapeutic utilities thereof.